Hepatitis E is endemic in many countries throughout the developing world, in particular on the continents of Africa and Asia. The disease generally affects young adults and has a very high mortality rate, up to 20%, in pregnant women (Mast, 1993; Tsega, 1992; Khuroo, 1981). The causative agent, hepatitis E virus (HEV), is transmitted primarily by the fecal-oral route, often through contaminated water (Purcell, 1996)). The availability of sensitive serological tests for HEV has permitted detailed assessment of the prevalence of HEV infection. In regions where HEV is endemic, anti-HEV antibodies have been detected in sera from convalescent individuals as well as from the general population. Surprisingly, in industrialized countries, such as the United States, where hepatitis E is not endemic, a significant proportion of healthy individuals within the general population are seropositive (up to 20% in some areas (Thomas, 1997; Mast, 1997)). However, clinical hepatitis E is rare in these countries and individuals usually acquire their infection during travel to a region that is endemic or epidemic for HEV.
It has been suggested that animals serve as reservoirs for HEV in some regions, and human infections may, in part, be zoonoses. There have been several reports of HEV-specific antibody (anti-HEV) in animals (Clayson, 1995; Karetnyi, 1993; Arankalle, 1994; Kabrane-Lazizi, 1999). Furthermore, an HEV-like virus was recently isolated from naturally infected swine in the United States (Meng, 1997). The four genotypes of HEV identified based on nucleotide sequence diversity are Asian/African, Mexican, U.S. and the New Chinese. To-date, only one serotype of HEV has been found. Therefore, it may be possible to produce a broadly protective vaccine in the near future.
Studies have shown that passively transferred anti-HEV significantly reduced virus shedding in feces, and abrogated disease in non-human primates challenged with a high dose of HEV (Tsarev, 1994). The findings suggest that immunoglobulin preparations, similar to those used for protection against hepatitis A, would be efficacious against hepatitis E. Field studies in India performed using pools of normal serum immunoglobulin collected from HEV endemic regions did not show protection from HEV infection or disease (Joshi, 1985; Khuroo, 1992; Zhuang, 1991). It is likely that the titer of anti-HEV antibodies in those studies was too low to have a protective effect. As pooled normal human serum is unlikely to be useful as an immunoprophylactic reagent against HEV, neutralizing monoclonal antibodies to HEV could be used to produce a high titer immunoglobulin preparation which might protect against hepatitis E virus.
Antibody phage display libraries provide a powerful tool for the isolation of human antibodies to important viral pathogens. Antibody phage display libraries are constructed from variable heavy and light chain antibody genes using a phage display vector specifically designed for the expression of antibody fragments to an antigen (Winter, 1994; de Kruif, 1996; Burton, 1994). From such libraries, large numbers of human monoclonal antibodies to an antigen of choice can be cloned and isolated. The technique provides new opportunities to produce high affinity human monoclonal antibodies for use in passive immunoprophylaxis. To date, monoclonal antibodies to a number of viral antigens, for example, human immunodeficiency virus-1 gp120 (Thompson, 1996; Geoffroy, 1994; Burton, 1991; Ditzel, 1997), measles virus (Bender, 1994), and respiratory syncitial virus F protein (Crowe, 1994), have been isolated.
The identification of neutralization epitopes of HEV provides an alternative method for the production of neutralizing antibodies to HEV.